Method for producing 2-(2-aminopyrimidin-4-yl)-1H-indole-5-carboxylic acid derivatives

ABSTRACT

This disclosure relates to a novel process for obtaining a compound of formula I: 
                         
wherein the values of R1, R2, and R3 and P are as described in the specification, and intermediates thereof.

BACKGROUND OF THE INVENTION

It is known that indole derivatives are used as units for the synthesis of active pharmaceutical ingredients. For example, 2-(2-aminopyrimidin-4-yl)-1H-indole-5-carboxylic acids or their salts are important units for the preparation of IkB kinase inhibitors (see WO 01/30774 A1):

2-(2-Aminopyrimidin-4-yl)-1H-indole-5-carboxylic acids can be prepared by classical Fischer indole synthesis starting from the corresponding 4-acetylpyrimidines (III) and 4-hydrazinobenzoic acid (II) (see scheme 1):

One disadvantage here is the severe reaction conditions which are required for a full conversion. Secondly, the products of this reaction are obtained in a mixture with the corresponding oligomers, which leads to a poor isolability, especially with regard to the filtration times. Moreover, these oligomers, owing to the low solubility of 2-(2-aminopyrimidin-4-yl)-1H-indole-5-carboxylic acids in organic solvents, can only be removed with difficulty and are entrained as an impurity in the further reactions, in some cases up to the active ingredient.

SUMMARY OF THE INVENTION

The invention relates to a process for preparing compounds of the formula I and to novel intermediates in obtaining the compound of the formula I. The indole derivatives mentioned are suitable intermediates for preparing Ikb kinase inhibitors (WO 01/30774 A1; WO2004/022553).

DETAILED DESCRIPTION OF THE INVENTION

It is an object of the present invention to find an industrial process for preparing the compounds of the formula I which does not have the disadvantages mentioned.

A process has now been found for obtaining the compound of the formula I

where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₁₂)-alkyl,     -   3) —(C₆-C₁₄)-aryl,     -   4) —(C₃-C₈)-cycloalkyl or     -   5) a 4-to 15-membered Het ring, -   R2 and R3 are the same or different and are each independently     -   1) a hydrogen atom,     -   2) (C₁-C₁₂)-alkyl,     -   3) —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-, di- or         trisubstituted by —(C₁₋₆)-alkyl,     -   4) —(C₃-C₈)-cycloalkyl or     -   5) a 4-to 15-membered Het ring, -   P is a hydrogen atom or a nitrogen protecting group,     which comprises -   a) reacting a boronoindole of the formula IV

-   -   in which R1 is as defined in formula I,     -   R4 and R5 are the same or different and are each independently     -   1) —OH,     -   2) —O—(C₁-C₁₂)-alkyl,     -   3) —O—(C₆-C₁₄)-aryl,     -   4) —O—(C₃₋₈)-cycloalkyl,     -   5) —(C₁-C₁₂)-alkyl or     -   6) —O-Het, where Het is a 4-to 15-membered Het ring, or     -   R4 and R5, together with the boron atom to which they are         bonded, form a ring having 4, 5, 6 or 7 carbon atoms in the ring         and the ring may, instead of the particular carbon atoms,         contain two oxygen atoms or two oxygen atoms and one nitrogen         atom,     -   P is a hydrogen atom or a nitrogen protecting group, with an         aminopyrimidine of the formula V

-   -   in which R2 and R3 are each as defined in formula I and     -   X is 1) halogen,         -   2) —O—SO₂—R2 or         -   3) —O—C(O)—R2,     -   and detaching any nitrogen protecting group present, or

-   b) reacting a boronoindole of the formula IV with a pyrimidine of     the formula VI

-   -   in which X is as defined in formula V and     -   Y is 1) halogen,         -   2) —O—SO₂—R2, or         -   3) —O—C(O)—R2     -   to give a compound of the formula VII

-   -   in which R1 and P are each as defined in formula IV and Y is as         defined in the compound of the formula VI,     -   and then reacting the compound of the formula VII with an amine         of the formula VIII

-   -   in which R2 and R3 are each as defined in formula I     -   to give a compound of the formula I and detaching any nitrogen         protecting group present, or

-   c) reacting the alkyne of the formula IX

-   -   in which R1 is as defined in formula I     -   with a pyrimidine of the formula (V) to give an alkyne of the         formula X

-   -   in which R1, R2 and R3 are each as defined in formula I,     -   and converting the compound of the formula X to the compound of         the formula I by ring closure, or

-   d) either isolating the compound of the formula I prepared by     processes a), b) or c) in free form or, in the case of the presence     of acidic or basic groups, converting it to physiologically     compatible salts.

The invention further relates to a process for obtaining the compound of the formula I where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₆)-alkyl,     -   3) phenyl or     -   4) —(C₃-C₆)-cycloalkyl, -   R2 and R3 are the same or different and are each independently a     hydrogen atom or     -   —(C₁-C₄)-alkyl,         wherein a boronoindole of the formula IV         in which R1 is as defined for formula I, -   R4 and R5 are the same or different and are each independently —OH     or     -   —(C₁-C₆)-alkyl, or -   R4 and R5, together with the boron atom to which they are bonded,     form a ring from the group of borolane, borinane, borepane,     borocane, [1,3,2]dioxaborolane, [1,3,2]dioxaborinane,     [1,3,2]dioxaborepane, [1,3,2]dioxaborocane or     [1,3,6,2]dioxazaborocane, -   P is 1) a hydrogen atom,     -   2) —C(O)—O—R6 in which R6 is         -   a) a hydrogen atom,         -   b) —(C₁-C₆)-alkyl,         -   c) —(C₆-C₁₄)-aryl where aryl is selected from the group of             phenyl, naphthyl, anthryl and fluorenyl, and in which aryl             is unsubstituted or mono-, di- or trisubstituted by             —(C₁-C₆)-alkyl,         -   d) —(C₃-C₆)-cycloalkyl or         -   e) a radical from the group of acridinyl, azepinyl,             azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,             benzofuranyl, benzothiofuranyl, benzothiophenyl,             benzoxazolyl, benzothiazolyl, benzotriazolyl,             benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl,             carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl,             quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,             chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,             dibenzofuranyl, dibenzothiophenyl,             dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl,             dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl,             furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,             1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,             isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,             isoindolyl, isoquinolinyl (benzimidazolyl),             isothiazolidinyl, 2-isothiazolinyl, isothiazolyl,             isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl,             naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,             1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,             1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,             oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,             phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,             phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,             pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,             pyridazinyl, pyridooxazolyl, pyridoimidazolyl,             pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl,             pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,             tetrahydrofuranyl, tetrahydroisoquinolinyl,             tetrahydroquinolinyl, tetrahydropyridinyl,             6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,             1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,             thianthrenyl, thiazolyl, thienyl, thienothiazolyl,             thienooxazolyl, thienoimidazolyl, thiomorpholinyl,             thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,             1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or             xanthenyl,     -   3) SO₃—R6,     -   4) —O—SO₂—R6,     -   5) —Si—R6 or     -   6) benzyl -   is reacted with an aminopyrimidine of the formula V -   in which R2 and R3 are the same or different and are each     independently a hydrogen atom or —(C₁-C₄)-alkyl, and -   X is Cl, Br, I, —O-tosylate, —O-mesylate or —O-acetate, and -   any nitrogen protecting group present is detached.

The invention further relates to a process for obtaining the compound of the formula I where

-   R1 is a hydrogen atom or ethyl, -   R2 and R3 are the same or different and are each independently a     hydrogen atom or     -   —(C₁-C₄)-alkyl,         wherein a boronoindole of the formula IV -   in which R1 is as defined for formula I, -   R4 and R5 are the same and are each —OH, and -   P is 1) a hydrogen atom,     -   2) —O-tosylate or     -   3) benzyl         is reacted with an aminopyrimidine of the formula V -   in which R2 and R3 are the same or different and are each     independently a hydrogen atom or —(C₁-C₄)-alkyl, and -   X is Cl, Br, I, —O-tosylate, —O-mesylate or —O-acetate, and     any nitrogen protecting group present is detached.

The invention further relates to a process for obtaining the compound of the formula I where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₆)-alkyl,     -   3) phenyl or     -   4) —(C₃-C₆)-cycloalkyl, -   R2 and R3 are the same or different and are each independently a     hydrogen atom or     -   —(C₁-C₄)-alkyl,         wherein a boronoindole of the formula IV         in which R1 is as defined for formula I, -   R4 and R5 are the same or different and are each independently —OH     or     -   —(C₁-C₆)-alkyl, or -   R4 and R5, together with the boron atom to which they are bonded,     form a ring from the group of borolane, borinane, borepane,     borocane, [1,3,2]dioxaborolane, [1,3,2]dioxaborinane,     [1,3,2]dioxaborepane, [1,3,2]dioxaborocane or     [1,3,6,2]dioxazaborocane, -   P is 1) a hydrogen atom,     -   2) —C(O)—O—R6 in which R6 is         -   a) a hydrogen atom,         -   b) —(C₁-C₆)-alkyl,         -   c) —(C₆-C₁₄)-aryl where aryl is selected from the group of             phenyl, naphthyl, anthryl and fluorenyl, and in which aryl             is unsubstituted or mono-, di- or trisubstituted by             —(C₁-C₆)-alkyl,         -   d) —(C₃-C₆)-cycloalkyl or         -   e) a radical from the group of acridinyl, azepinyl,             azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,             benzofuranyl, benzothiofuranyl, benzothiophenyl,             benzoxazolyl, benzothiazolyl, benzotriazolyl,             benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl,             carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl,             quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,             chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,             dibenzofuranyl, dibenzothiophenyl,             dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl,             dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl,             furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,             1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,             isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,             isoindolyl, isoquinolinyl (benzimidazolyl),             isothiazolidinyl, 2-isothiazolinyl, isothiazolyl,             isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl,             naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,             1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,             1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,             oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,             phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,             phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl,             pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,             pyridazinyl, pyridooxazolyl, pyridoimidazolyl,             pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl,             pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,             tetrahydrofuranyl, tetrahydroisoquinolinyl,             tetrahydroquinolinyl, tetrahydropyridinyl,             6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,             1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,             thianthrenyl, thiazolyl, thienyl, thienothiazolyl,             thienooxazolyl, thienoimidazolyl, thiomorpholinyl,             thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,             1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or             xanthenyl,         -   3) SO₃—R6,         -   4) —O—SO₂—R6,         -   5) —Si—R6 or         -   6) benzyl             is reacted with a pyrimidine of the formula VI in which -   X is Cl, Br, I, —O-tosylate, —O-mesylate or —O-acetate, and -   Y is Cl, Br, I, —O-tosylate, —O-mesylate or O-acetate,     to give a compound of the formula VII and then the compound of the     formula VII is reacted with an amine of the formula VIII in which R2     and R3 are the same or different and are each independently a     hydrogen atom or —(C₁-C₄)-alkyl to give a compound of the formula I     and any nitrogen protecting group present is detached.

The invention further relates to a process for obtaining the compound of the formula I where

-   R1 is a hydrogen atom or ethyl, -   R2 and R3 are the same or different and are each independently a     hydrogen atom or     -   —(C₁-C₄)-alkyl,         wherein a boronoindole of the formula IV -   in which R1 is as defined for formula I, -   R4 and R5 are the same and are each —OH, and -   P is 1) a hydrogen atom,     -   2) —O-tosylate or     -   3) benzyl,         is reacted with a pyrimidine of the formula VI in which -   X is Cl, Br, I, —O-tosylate, —O-mesylate or —O-acetate, and -   Y is Cl, Br, I, —O-tosylate, —O-mesylate or O-acetate,     to give a compound of the formula VII and then the compound of the     formula VII is reacted with an amine of the formula VIII in which R2     and R3 are the same or different and are each independently a     hydrogen atom or —(C₁-C₄)-alkyl to give a compound of the formula I     and any nitrogen protecting group present is detached.

Process step a) is performed, for example, under the reaction conditions as described by B. Jiang and C. Yang in Heterocycles, Vol. 53, 2000, p. 1489-1498.

The reaction of the boronoindoles (IV) with the pyrimidine derivatives (V) is preferably performed in the presence of catalytic amounts of palladium or nickel compounds such as Pd(PPh₃)₄, Pd₂(dba)₃, Pd(OAc)₂ or PdCl₂/TPPTS.

The reaction temperature is from 40° to 80° C., preferably from 60° C. to 70° C. The reaction time is generally from 2 to 3 hours according to the composition of the mixture and the selected temperature range. Suitable solvents are, for example, methanol, ethanol or toluene. The molar ratio of the compound of the formula IV to the compound of the formula V is, for example, from 1:1 to 1:1.3.

The purity is determined by HPLC.

The compounds of the formula IV are either known or can be prepared, for example, by reacting the corresponding N-protected indole-5-carboxylic acid derivatives (XI) with bases such as LDA, LiTMP or LiHMDS, and subsequent reaction with boric esters such as triisopropyl borate or trimethyl borate (scheme 5).

It has been found to be more advantageous to remove the nitrogen protecting group before the actual reaction, since, in this case, the indole (XI) which forms as a by-product during the coupling as a result of detachment of the borono group is formed to a lower degree, which results in a higher yield.

The compounds of the formula V are either known or can be prepared by reacting pyrimidine derivatives (VI) with amines VIII and subsequent removal from the isomer XII, for example by chromatography or steam distillation (see scheme 6).

It is also possible to perform the actual reaction with mixtures of (V) and (XII), since it has been found that, surprisingly, the isomer (XII), under the reaction conditions of this coupling, does not react to give (XIII), which is an isomer of (I) (scheme 7)

Process step b) is performed analogously to a).

Process step c) is performed, for example, under the reaction conditions as described by I. Beletskaya et al. in Tetrahedron Letters 44 (2003) 501-5013. The reaction of the compounds of the formula IX with the pyrimidine derivatives (V) is effected preferably in the presence of metal catalysts such as Pd(OAc)₂ or CuI and triphenylphosphine or TPPTS. The ring closure of (X) to (I) can be effect, for example, by addition of bases such as KOtBu or KHMDS.

The reaction temperature is from 15° C. to 30° C., preferably from 20° C. to 25° C. The reaction time is generally from 20 to 24 hours according to the composition of the reaction mixture and the selected temperature range. Suitable solvents are, for example, N-methylpyrrolidone (NMP) or dimethylformamide (DMF).

The purity is determined by high-pressure liquid chromatography (HPLC).

The preparation of physiologically compatible salts from compounds of the formula I capable of salt formation, including their stereoisomeric forms, according to process step d) is effected in a manner known per se. The compounds of the formula I form stable alkali metal salts, alkaline earth metal salts or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, hydrogencarbonates, alkoxides and ammonia, or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for instance lysine, ornithine or arginine. When the compounds of the formula I have basic groups, it is also possible to prepare stable acid addition salts with strong acids. Useful acids for this purpose include both inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, hemisulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid, trifluoromethyl-sulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, oxalic acid, tartaric acid, succinic acid, glycerolphosphoric acid, lactic acid, malic acid, adipic acid, citric acid, fumaric acid, maleic acid, gluconic acid, glucuronic acid, palmitic acid or trifluoroacetic acid. Preference is given to alkali metals and alkaline earth metals or ammonium salts. Examples of alkali metals and alkaline earth metals are Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr or Ba. An example of an ammonium salt is NH₄.

The invention further relates to a process for obtaining the compound of the formula I, wherein

-   a) an aminobenzoic acid of the formula XIV

-   -   where R1 is as defined in formula I and X is as defined in         formula V, is reacted with trimethylsilylacetylene to give a         compound of the formula XVI

-   -   where R1 is as defined in formula I and Me is methyl, and

-   b) the compound of the formula XVI is converted to an alkyne of the     formula IX where R1 is as defined in formula I, and

-   c) the alkyne of the formula IX is reacted with a pyrimidine of the     formula (V) to give an alkyne of the formula X in which R1, R2 and     R3 are each as defined in formula I, and the compound of the formula     X is converted to the compound of the formula I by ring closure.

The compounds of the formula IX are either known or can be prepared by reacting aminobenzoic acid derivatives (XIV) with trimethylsilylacetylene (XV) and subsequently detaching the silyl protecting group (scheme 8)

The term “nitrogen protecting group” is understood to mean amine protecting groups customary for P, as described in T. Greene, “Protective Groups in Organic Synthesis”. Further examples of nitrogen protecting groups are the radicals 2) to 6) for P as the radical in the compound of the formula II.

The term “catalytic amounts of palladium or nickel compounds” is understood to mean from 0.03 to 0.3 mol (for example based on moles of the compound of the formula IV) of the following compounds Pd(PPh₃)₄, Pd₂(dba)₃, Pd(OAc)₂ or PdCl₂/TPPTS.

The term “metal catalysts” is understood to mean, for example, from 0.03 to 0.3 mol (for example based on moles of the compound of the formula IV) of the following compounds Pd(PPh₃)₄, Pd₂(dba)₃, Pd(OAc)₂ or PdCl₂/TPPTS.

The terms “—(C₁-C₁₂)-alkyl” are understood to mean hydrocarbon radicals whose carbon chain is straight or branched and contains from 1 to 12 carbon atoms. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, 2,3-dimethylbutane, neohexyl, heptyl, octyl, nonanyl, decanyl or dodecanyl.

The term “(C₃-C₈)-cycloalkyl” is understood to mean radicals such as compounds which derive from 3-to 8-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The terms “—(C₆-C₁₄)-aryl” or “aryl” are understood to mean aromatic carbon radicals having from 6 to 14 carbon atoms in the ring. —(C₆-C₁₄)-Aryl radicals are, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, anthryl or fluorenyl.

Naphthyl radicals and especially phenyl radicals are preferred aryl radicals. The term “4-to 15-membered Het ring” are understood to mean ring systems which have from 4 to 15 carbon atoms, are present in one, two or three ring systems bonded to one another and contain one, two, three or four identical or different heteroatoms from the group of oxygen, nitrogen and sulfur. Examples of these ring systems are the acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, benzoimidazolyl, isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolylor xanthenyl radicals.

The term “R4 and R5, together with the boron atom to which they are bonded, form a ring having 4, 5, 6 or 7 carbon atoms in the ring and the ring may, instead of the particular carbon atoms, contain two oxygen atoms or two oxygen atoms and one nitrogen atom” is understood to mean ring systems which derive, for example, from borolane, borinane, borepane, borocane, [1,3,2]dioxaborolane, [1,3,2]dioxaborinane, [1,3,2]-dioxaborepane, [1,3,2]dioxaborocane or [1,3,6,2]dioxazaborocane.

The invention further relates to novel compounds of the formula II

or a physiologically compatible salt of the compound of the formula II, where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₁₂)-alkyl,     -   3) —(C₆-C₁₄)-aryl,     -   4) —(C₃-C₈)-cycloalkyl or     -   5) a 4-to 15-membered Het ring,         with the proviso that R1 is not a hydrogen atom when P is a         hydrogen atom, and D is —N(R2)-R3 in which R2 is a hydrogen atom         and R3 is —(C₁-C₄)-alkyl, -   P is 1) a hydrogen atom,     -   2) —C(O)—O—R6 in which R6 is         -   a) a hydrogen atom,         -   b) —(C₁-C₁₂)-alkyl,         -   c) —(C₆₋₁₄)-aryl where aryl is unsubstituted or mono-, di-             or tri-substituted by —(C₁-C₆)-alkyl,         -   d) —(C₃-C₈)-cycloalkyl or         -   e) a 4-to 15-membered Het ring,     -   3) —SO₃—R₆,     -   4) —O—SO₂—R₆,     -   5) —Si—R₆ or     -   6) benzyl, -   D is 1) —N(R2)-R3,     -   2) halogen     -   3) —O—SO₂—R2 or     -   4) —O—C(O)—R2,     -   in which R2 and R3 are the same or different and are each         independently         -   a) a hydrogen atom,         -   b) —(C₁-C₁₂)-alkyl,         -   c) —(C₆₋₁₄)-aryl where aryl is unsubstituted or mono-, di-             or trisubstituted by —(C₁-C₆)-alkyl,         -   d) —(C₃-C₆)-cycloalkyl or         -   e) a 4-to 15-membered Het ring.

A further aspect of the invention relates to novel compounds of the formula II in which

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₆)-alkyl,     -   3) phenyl or     -   4) —(C₃-C₆)-cycloalkyl,         with the proviso that R1 is not a hydrogen atom when P is a         hydrogen atom and D is —N(R2)-R3 in which R2 is a hydrogen atom         and R3 is —(C₁-C₄)-alkyl, -   D is chlorine, bromine, iodine, fluorine or —N(R2)-R3 where     -   R2 and R3 are the same or different and are each independently     -   a hydrogen atom or —(C₁-C₄)-alkyl, -   P is 1) a hydrogen atom,     -   2) —C(O)—O—R6 in which R6 is         -   a) a hydrogen atom,         -   b) —(C₁-C₆)-alkyl,         -   c) —(C₆-C₁₄)-aryl where aryl is selected from the group of             phenyl, naphthyl, anthryl and fluorenyl, and in which aryl             is unsubstituted or mono-, di- or trisubstituted by             —(C₁-C₆)-alkyl,         -   d) —(C₃-C₆)-cycloalkyl or         -   e) a radical from the group of acridinyl, azepinyl,             azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,             benzofuranyl, benzothiofuranyl, benzothiophenyl,             benzoxazolyl, benzothiazolyl, benzotriazolyl,             benzo-tetrazolyl, benzoisoxazolyl, benzoisothiazolyl,             carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl,             quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,             chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,             dibenzofuranyl, dibenzothiophenyl,             dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl,             dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl,             furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,             1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,             isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,             isoindolyl, isoquinolinyl, benzimidazolyl, isothiazolidinyl,             2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl,             2-isoxazolinyl, morpholinyl, naphthyridinyl,             octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,             1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,             oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl,             pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,             phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,             piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl,             pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl,             pyridazinyl, pyridooxazolyl, pyridoimidazolyl,             pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl,             pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,             tetrahydrofuranyl, tetrahydroisoquinolinyl,             tetrahydroquinolinyl, tetrahydropyridinyl,             6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,             1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,             thianthrenyl, thiazolyl, thienyl, thienothiazolyl,             thienooxazolyl, thienoimidazolyl, thiomorpholinyl,             thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,             1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl or             xanthenyl,     -   3) —SO₃—R6,     -   4) —O—SO₂—R6,     -   5) —Si—R6 or     -   6) benzyl.

A further aspect of the invention relates to novel compounds of the formula II in which

-   R1 is a hydrogen atom or ethyl,     with the proviso that R1 is not a hydrogen atom when P is a hydrogen     atom and D is —N(R2)-R3 in which R2 is a hydrogen atom and R3 is     —(C₁-C₄)-alkyl, -   D is chlorine or —N(R2)-R3 where     -   R2 and R3 are the same or different and are each independently a         hydrogen atom or —(C₁-C₄)-alkyl, -   P is a hydrogen atom, —O-tosylate or benzyl.

The compounds of the formula II are obtainable, for example, by process variants a), c) or d) for preparing the compound of the formula I, or arise as intermediates of the formula VII in process variant b) for preparing the compound of the formula I.

The invention further relates to novel compounds of the formula IV

where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₁₂)-alkyl,     -   3) —(C₆-C₁₄)-aryl,     -   4) —(C₃-C₈)-cycloalkyl or     -   5) a 4-to 15-membered Het ring, -   R4 and R5 are the same or different and are each independently     -   1) —OH,     -   2) —O—(C₁₋₁₂)-alkyl,     -   3) —O—(C₆-C₁₄)-aryl,     -   4) —O—(C₃-C₈)-cycloalkyl,     -   5) —(C₁-C₁₂)-alkyl or     -   6) —O-Het, -   R4 and R5, together with the boron atom to which they are bonded,     form a ring having 4, 5, 6 or 7 carbon atoms in the ring and the     ring may, instead of the particular carbon atoms, contain two oxygen     atoms or two oxygen atoms and one nitrogen atom, -   P is 1) a hydrogen atom,     -   2) —C(O)—O—R6, in which R6 is         -   a) a hydrogen atom,         -   b) —(C₁-C₁₂)-alkyl,         -   c) —(C₆₋₁₄)-aryl where aryl is unsubstituted or mono-, di-             or tri-substituted by —(C₁-C₆)-alkyl,         -   d) —(C₃-C₈)-cycloalkyl or         -   e) a 4-to 15-membered Het ring,     -   3) —SO₃—R₆,     -   4) —O—SO₂—R₆,     -   5) —Si—R₆ or     -   6) benzyl,         with the proviso that R4 and R5 are not —OH or         —O—(C₁-C₁₂)-alkyl, when P is —C(O)—O—(C₁-C₁₂)-alkyl or R1 is         —(C₁-C₁₂)-alkyl.

The invention further relates to novel compounds of the formula IV where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₈)-alkyl,     -   3) —(C₆-C₁₄)-aryl where aryl is selected from the group of         phenyl, naphthyl, anthryl and fluorenyl,     -   4) —(C₃-C₆)-cycloalkyl or     -   5) a 4-to 15-membered Het ring, in which Het is a radical from         the group of acridinyl, azepinyl, azetidinyl, aziridinyl,         benzimidazalinyl, benzimidazolyl, benzofuranyl, benzothiouranyl,         benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,         benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, carbazolyl,         4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl,         4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl,         chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl,         dibenzothiophenyl, dihydrofuran[2,3-b]-tetrahydrofuranyl,         dihydrofuranyl, dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl,         furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,         1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,         isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,         isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl,         2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl,         2-isoxazolinyl, morpholinyl, naphthyridinyl,         octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,         1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,         oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl,         phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,         phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,         piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl,         pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,         pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,         pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl,         pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,         tetrahydroisoquinolinyl, tetrahydroquinolinyl,         tetrahydropyridinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,         1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,         thianthrenyl, thiazolyl, thienyl, thienothiazolyl,         thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl,         triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,         1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl, -   R4 and R5 are the same or different and are each independently     -   1) —OH,     -   2) —O—(C₁-C₁₂)-alkyl,     -   3) —O—(C₆-C₁₄)-aryl, where aryl is as defined above,     -   4) —O—(C₃-C₆)-cycloalkyl,     -   5) —(C₁₋₆)-alkyl or     -   6) —O-Het, where Het is a 4-to 15-membered Het ring and is as         defined above, or -   R4 and R5, together with the boron atom to which they are bonded,     form a ring from the group of borolane, borinane, borepane,     borocane, [1,3,2]dioxaborolane, [1,3,2]dioxaborinane,     [1,3,2]dioxaborepane, [1,3,2]dioxaborocane or     [1,3,6,2]dioxazaborocane, and     -   P is a hydrogen atom.

The invention further relates to novel compounds of the formula X

where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₁₂)-alkyl,     -   3) —(C₆-C₁₄)-aryl,     -   4) —(C₃-C₈)-cycloalkyl or     -   5) a 4-to 15-membered Het ring, -   R2 and R3 are the same or different and are each independently     -   1) a hydrogen atom,     -   2) (C₁-C₁₂)-alkyl,     -   3) —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-, di- or         trisubstituted by —(C₁₋₆)-alkyl,     -   4) —(C₃-C₈)-cycloalkyl or     -   5) a 4-to 15-membered Het ring.

The compounds of the formula X are obtainable, for example, through process variant c) for preparing the compound of the formula I.

The invention further relates to novel compounds of the formula XVI

where

-   R1 is 1) a hydrogen atom,     -   2) —(C₁-C₁₂)-alkyl,     -   3) —(C₆-C₁₄)-aryl,     -   4) —(C₃-C₈)-cycloalkyl or     -   5) a 4-to 15-membered Het ring.

The compounds of the formulae II, IV, X, XI or XVI are suitable as intermediates for preparing IkB kinase inhibitors, as described, for example, in WO 01/30774 A1.

The invention is illustrated in detail hereinafter with reference to examples. End products are determined generally by ¹H NMR (400 MHz, in DMSO-D6). Temperatures are in degrees Celsius; RT means room temperature (22° C. to 26° C.). Abbreviations used are either explained or correspond to the customary conventions.

List of abbreviations: Dba dibenzylideneacetone KHMDS potassium hexamethyldisilazide KOtBu potassium tert-butoxide LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazide LiTMP lithium tetramethylpiperazide OTos

OMes

OAc

Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0) Tos

TPPTS triphenylphosphine trisulfonate THF tetrahydrofuran

EXAMPLE 1 Synthesis of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate

28 g (114 mmol) of 2-borono-5-ethoxycarbonylindole, 12 g (113 mmol) of sodium carbonate and 17.2 g of 2,4-(113 mmol) dichloropyrimidine were initially charged in 412 ml of ethanol. The clear solution was freed of oxygen by vigorous stirring and passing argon through (20 minutes). At RT, 2.67 g of tetrakis(triphenylphosphine)palladium(0) were added. The mixture was heated to from 65° C. to 70° C. for 2 hours (h). Subsequently, 112 ml of water and 112 ml of 30% hydrochloric acid were added and the mixture was cooled to 0° C. After filtration and drying under reduced pressure, 37.3 g (93% of theory) of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate were obtained (HPLC >96%).

The purity was determined by high-pressure liquid chromatography (HPLC):

Column: Waters Symetry Shield RP8 3.9 * 150 Temperature: 40° C. Flow rate: 1 ml/min Injection volume: 10 μl Pressure: 90 bar UV: 254 nm Eluent: A: Water/trifluoroacetic acid (0.05%) B: Acetonitrile/trifluoroacetic acid (0.05%) Time (min)  0 15 20 25 30 A (%) 80 25 25 80 80 B (%) 20 75 75 20 20 Retention time of 12.6 min title compound:

EXAMPLE 2 Synthesis of ethyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate

30 g (95.4 mmol) of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate were initially charged and suspended in 150 ml of ethanol. 53.9 g of methylamine solution in ethanol (8 M) were added to this suspension which was heated to from 75° C. to 80° C. in an autoclave for 4 h. After concentration and washing with ethanol, 29.7 g of ethyl 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylate were obtained (97.6 HPLC area %). LCMS: [M+H]⊕ 297.12

HPLC method as in example 1; retention time of title compound: 5.8 min

EXAMPLE 3 Synthesis of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid sodium salt

25 g of ethyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate were admixed with 200 ml of ethanol and 24.5 g of 33% sodium hydroxide solution, and heated to from 65° C. to 70° C. for 4 h. After cooling, the mixture was filtered with suction and the precipitate was washed with 15 ml of ethanol/water (9:1). 24.5 g (87.6% of theory) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid sodium salt were obtained (98.1 HPLC area %). LCMS: [M+H]⊕ 269.10

HPLC method as in example 1; retention time of title compound: 3.3 min

EXAMPLE 4 Synthesis of methyl 4-amino-3-trimethylsilylethynylbenzoate

5.83 g (20 mmol) of methyl 4-aminobenzoate, 20.2 g (198 mmol) of triethylamine and 80 ml of toluene were initially charged. The clear solution was freed of oxygen by vigorous stirring and passing argon through (20 minutes). At an internal temperature of 20° C., 3.2 g (33 mmol) of trimethylsilylacetylene, 76 mg of copper(I) iodide and 52 mg of triphenylphosphine were added. After aqueous workup, 5.45 g of 4-amino-3-trimethylsilylethynylbenzoate were obtained (HPLC: >99 area %). HPLC method as in example 1.

EXAMPLE 5 Synthesis of methyl 4-amino-3-ethynylbenzoate

1.9 g (7.7 mmol) of methyl 4-amino-3-trimethylsilylethynylbenzoate were initially charged in 20 ml of tetrahydrofuran (THF). At from 5° C. to 8° C., 8.45 ml (8.5 mmol) of tetrabutylammonium fluoride solution (1 M in THF) were added dropwise within 5 minutes. After 25 min at 2° C., 438 ml of acetic acid were added. After addition of water and extraction with dichloromethane, and after removal of the solvent, 1.35 g of methyl 4-amino-3-ethynylbenzoate were obtained. HPLC method as in example 1.

EXAMPLE 6 Synthesis of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)-ethynylbenzoate

3.0 g (17 mmol) of methyl 4-amino-3-ethynylbenzoate and 2.6 g (19 mmol) of 4-chloro-2-methylaminopyrimidine were initially charged in 20 ml of dimethylformamide (DMF) and 8.7 g (85 mmol) of triethylamine, and degassed with argon while stirring for 5 min. Subsequently, 65 mg of copper(I) iodide and 20 mg of tetrakis(triphenylamine)palladium(0) were added and the mixture was heated to 71° C. for 3 h. After aqueous workup, 4.1 g of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate were obtained. (HPLC: 99.7 area %) HPLC method as in example 1.

EXAMPLE 7 Synthesis of methyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate by cyclizing methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate

73 mg (0.7 mmol) of potassium tert-butoxide were dissolved in 1 ml of NMP and admixed with a solution of 140 mg (0.5 mmol) of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate in 1 ml of NMP. Subsequently, stirring was continued at RT for 24 h. Aqueous workup afforded 115 mg of methyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate (HPLC: 92.3 area %).

EXAMPLE 8 Synthesis of 2-borono-5-ethoxycarbonylindole

150 g (519 mmol) of N-Boc-5-ethoxycarbonylindole and 192 ml (833 mmol) of triisopropyl borate in 350 ml of toluene were admixed at from 5° C. to 10° C. with 350 ml of a 1.8 molar solution of LDA in THF. The mixture was stirred for a further 5 min and the reaction mixture was added to a solution of 278 g of 30% hydrochloric acid and 940 ml of water. Subsequently, the mixture was stirred at from 5° C. to 10° C. for 30 min. Thereafter, the mixture was filtered and the filtercake was suspended in 530 ml of ethanol. This suspension was added at 40° C. to a solution of 500 ml of 30% hydrochloric acid and 224 ml of ethanol. Subsequently, the mixture was stirred at from 40° C. to 45° C. for 2.5 h and admixed at 30° C. with 380 ml of water. The mixture was then cooled to from 10° C. to 15° C., stirred at this temperature for 30 min and filtered. Drying under reduced pressure afforded 79.5 g (61% of theory) of 2-borono-5-ethoxycarbonylindole (HPLC: 92.7 area %). 

What is claimed is:
 1. The compound ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate. 